Growth factors and their receptors are essential for epithelial cell function. Abnormalities in expression of epidermal growth factor receptor (EGFR) and its downstream signaling pathways contribute to progression, invasion and maintenance of the malignant phenotype in human head and neck cancers. Agents directed against EGFR are promising biologically-based treatments. This project is designed to determine whether the EGFR kinase inhibitor ZD1839 (Iressa) can suppress the activity of EGFR, thereby inhibiting the downstream signaling pathways thought to be important in head and neck cancer carcinogenesis and halting disease progression. Data suggest that EGFR over-expression may be closely linked with c-Src and Pak1 kinases in head and neck cancer, and that ZD1839 may block EGFR-linked stimulation of these kinases. These data support the hypothesis that activation of the EGF receptor family stimulates the Src and Pakl signaling pathways, leading to increased cell survival, mitogenesis, motility and development of malignant phenotypes of head and neck cancer cells. We hypothesize that these phenotypic changes can be suppressed or reversed by ZD1839. To address these hypotheses, we propose the following specific aims: Specific Aim 1. To evaluate the role of the EGFR-Src and MAPK pathways in head and neck cancer cells and determine whether the EGFR kinase inhibitor ZD1839 (Iressa) acts through modulation of Src and MAPK activity. Specific Aim 2. To evaluate the role of the EGFR-Pakl pathway in motility and invasion of head and neck cancer cells and determine whether ZD1839 acts through modulation of Pakl activity. Specific Aim 3. To evaluate the chemopreventive activity ZD1839 in patients with oral premalignant lesions. These studies will delineate the mechanisms through which EGFR regulates growth, motility and survival of head and neck cancer cells and will provide a novel rationale for therapy of preneoplastic and malignant human head and neck tumors with an EGFR inhibitor. This work is designed to develop a novel strategy for prevention of head and neck carcinogenesis and establish the utility of mechanism-based signaling end points in prognosis of head and neck cancer and in evaluation of the biologic response to ZD1839.